RU2625747C2 - Granulates containing eslicarbazepine acetate - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: solid pharmaceutical granular composition is described. It contains eslicarbazepine acetate and excipients. In this case, at least 90% of the granules of the composition have a particle size of 1200 microns or less and at least 90% of the granules of the composition have a particle size of 90 microns or more and/or at least 50% of the granules of the composition have a particle size of 250 microns or more. These granules have a specific particle size, determined by the method of screening. Also, a method for producing a pharmaceutical granular composition of eslicarbazepine acetate is disclosed.

EFFECT: inventions provide a uniform distribution of the granules with a low number of small and large particles.

68 cl, 5 ex, 5 tbl, 7 dwg

Description

Field of Invention

The present invention relates to a solid pharmaceutical composition comprising eslicarbazepine acetate (ESL), wherein the composition is in the form of granules, and at least 90% of the granules of the composition have a particle size of about 90 microns or more, and / or at least 50 % of the granules of the composition have a particle size of about 250 microns or more. The present invention also relates to a method for producing a granular composition containing a pharmaceutically active substance, where at least 90% of the obtained granules have a particle size of about 90 microns or more, and / or where at least 50% of the obtained granules with a coating have particle size of about 250 microns or more.

BACKGROUND OF THE INVENTION

Document WO 2009/054743 relates to compositions for oral administration containing eslicarbazepine acetate, and to methods for their preparation. However, this document does not disclose granular compositions in which at least 90% of the granules of the composition have a particle size of about 90 microns and / or in which at least 50% of the granules of the composition have a particle size of about 250 microns or more.

SUMMARY OF THE INVENTION

According to a first aspect, the present invention provides a solid pharmaceutical composition for oral administration comprising eslicarbazepine acetate and one or more pharmaceutically acceptable excipients, the composition being in the form of granules, and where at least 90% of the granules of the composition have a particle size of at least at least about 90 microns, and / or where at least 50% of the granules of the composition have a particle size of at least about 250 microns.

The granules of the composition are larger than the known particles of eslicarbazepine acetate. Thus, the advantage is achieved that the granules dissolve more slowly. This means that in this case it is less likely that the patient taking these granules will feel an unpleasant taste of one of the ingredients of the composition. For example, the composition may be added to a patient’s food. Larger granules will dissolve more slowly in food, so when it is consumed, it is less likely that the food will have an unpleasant taste in one of the ingredients of the composition, for example, eslicarbazepine acetate.

The granules of the composition are relatively uniform in size, i.e. the difference between the largest and smallest particle sizes is relatively small. This means that the granules are easier to use because, for example, it is easier to sprinkle food on them or sprinkle food more evenly.

Granules are also easier to use in production processes. For example, they are easier to weigh. They are also easier to pack in sachets. In addition, such granules are easier to get from packaging, for example, from sachets. This means that the granules are easier to take, and the loss of the drug is also reduced compared to the use of powders that easily adhere to various surfaces, which is undesirable.

The term “granule” means a particle that is a stable aggregate (ie, a particle that remains completely or substantially in aggregated form after granulation using granulating liquids and drying) formed from many smaller particles. Usually in the particle forming the granule, particles of a smaller size can be identified. The term "granule" does not mean any limitation with respect to the size of the particles forming the granule. However, as will be described in more detail below, the granules according to the invention may have certain limitations with respect to the particle size of the granules. According to the invention, all granules of the composition, or at least granules having a particle size of 90 μm or more, contain eslicarbazepine acetate and one or more pharmaceutically acceptable excipients. These granules are formed during a granulation process in which granules are formed using eslicarbazepine acetate and one or more pharmaceutically acceptable excipients to increase the overall particle size of the components.

Preferably, the granules (i.e., each granule) contain a binder that helps to combine eslicarbazepine acetate and one or more pharmaceutically acceptable excipients and store them in the form of granules so that they do not break into smaller particles.

In one embodiment, at least 90% of the granules of the composition have a particle size of at least about 90 microns. In other embodiments, at least 90% of the granules of the composition have a particle size of at least about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230 , 240 or 250 microns.

In yet another embodiment, at least 50% of the granules of the composition have a particle size of at least about 250 microns. In other embodiments, at least 50% of the granules of the composition have a particle size of at least about 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 400 or 420 microns.

In yet another embodiment, at least 90% of the granules of the composition may have a particle size of about 1600 microns or less. Alternatively, at least 90% of the granules of the composition may have a particle size of about 1550, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 420, 400, 350 or 300 μm or less.

In an alternative embodiment, at least 80% of the granules of the composition have a particle size in the range of about 2000 microns. In other embodiments, at least 80% of the granules of the composition have a particle size in the range of about 1800, 1700, 1600, 1500, 1450, 1400, 1350, 1300, 1250, 1200, 1150, 1100, 1050, 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, or 100 microns.

Specialists know methods for measuring particle sizes of granules, as well as the distribution of granules in size, and these parameters can be easily measured. Such measurements can be carried out using, for example, several sieves or laser diffraction.

The composition contains eslicarbazepine acetate (IUPAC name: (S) -10-acetoxy-10,11-dihydro-5H-dibenz [b, f] azepine-5-carboxamide), which is known to those skilled in the art, methods for preparing eslicarbazepine acetate are also well known, for example , from US patent No. 5,753,646.

In one of the embodiments of the invention, the composition contains from about 2% to about 98 wt. % eslicarbazepine acetate. In some such embodiments, the composition comprises at least about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15 wt. % eslicarbazepine acetate. In some such embodiments, the composition comprises up to about 85%, 70%, 60%, 50%, 40%, 35%, 30%, 25%, 20% or 15 wt. % eslicarbazepine acetate. In certain embodiments of the invention, the amount of eslicarbazepine acetate in the composition may be from about 5 wt. % to about 85 wt. %, from about 7 wt. % to about 70 wt. %, from about 10 wt. % to about 50 wt. %, from about 5 wt. % to about 25 wt. % or from about 5 wt. % to about 15 wt. %

The composition may contain a filler. In one of the embodiments of the invention, the composition contains from about 2% to about 98 wt. % filler. In some such embodiments, the composition comprises at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75 wt. % filler. In some such embodiments, the composition comprises up to about 95%, 90%, 85%, 80%, or 75 wt. % filler. In certain embodiments, the composition comprises from about 15 wt. % to about 95 wt. %, from about 30 wt. % to about 90 wt. %, from about 50 wt. % to about 80 wt. %, from about 60 wt. % to about 90 wt. % or from about 70 wt. % to about 80 wt. % filler.

The excipient may be any pharmaceutically acceptable excipient. Specialists know the types of excipients that are commonly used in this field of activity for the preparation of pharmaceutical formulations. For example, the filler may be selected from microcrystalline cellulose, anhydrous lactose, Cellactose® 80 (combined and processed 75% microcrystalline cellulose and 25% lactose), isomalt, disubstituted calcium phosphate dihydrate, calcium carbonate, calcium lactate, dibasic anhydrous calcium phosphate, tricalcium phosphate calcium silicate, calcium sulfate, carbomer, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose, silicified microcrystalline cellulose, cellulose acetate, carob VA, chitosan, copovidone, corn starch, pre-gelatinized starch, dextrates, dextrin, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl monooleate, glyceryl monostearate hydroxymethyl hydroxyethyl cellulose hydroxyethyl hydroxyethyl cellulose hydroxyethyl hydroxyethyl cellulose hydroxyethyl hydroxyethyl hydroxyethyl cellulose hydroxyethyl hydroxyethyl hydroxyethyl hydroxyethyl hypromellose acetate succinate, kaolin, lactitol, anhydrous lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltitol, maltodext rin, maltose, mannitol, methyl cellulose, pectin, poloxamer, polycarbophil, polydextrose, poly-DL-lactic acid, polyethylene glycol, polyethylene oxide, polymethacrylates, polyoxyglycerides, polyvinyl alcohol, povidone, shellac, simethicone, sodium alginate, sodium alginate pre-gelatinized starch, sucrose, sugar grains, sulfobutyl ether beta-cyclodextrin, titanium dioxide, trehalose, microcrystalline wax, white wax, yellow wax, xanthan gum, xylitol and zein, or from any combination of these substances.

In certain embodiments of the invention, the filler is selected from one or more of the following materials: lactose, disubstituted calcium phosphate dihydrate, and isomalt. Preferably, the filler is lactose and disubstituted calcium phosphate dihydrate; or isomalt and disubstituted calcium phosphate dihydrate; or lactose and isomalt. More preferably, the filler is lactose and disubstituted calcium phosphate dihydrate.

When the filler contains lactose, the composition preferably contains from about 5 wt. % to about 90 wt. % lactose. In other embodiments, the composition comprises at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50 wt. % lactose. In certain embodiments of the invention, the composition comprises up to about 85%, 80%, 75%, 70%, 65%, 60% or 55 wt. % lactose. In certain embodiments, the amount of lactose in the composition may be from about 5 wt. % to about 80 wt. %, from about 15 wt. % to about 75 wt. %, from about 25 wt. % to about 60 wt. % or from about 40 wt. % to about 60 wt. %

When the filler contains disubstituted calcium phosphate dihydrate, the composition preferably contains from about 10 wt. % to about 50 wt. % disubstituted calcium phosphate dihydrate. More preferably, the amount of disubstituted calcium phosphate dihydrate in the composition is from about 15 wt. % to about 50 wt. %, from about 10 wt. % to about 35 wt. %, from about 15 wt. % to about 30 wt. %, from about 15 wt. % to about 25 wt. % or from about 20 wt. % to about 25 wt. %

When the filler contains isomalt, the composition preferably contains from about 5 wt. % to about 90 wt. % isomalt. In such specific embodiments of the invention, the composition comprises at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50 wt. % isomalt. In certain embodiments of the invention, the composition comprises up to about 85%, 80%, 75%, 70%, 65%, 60% or 55 wt. % isomalt. In certain embodiments, the amount of isomalt in the composition may be from about 5 wt. % to about 80 wt. %, from about 15 wt. % to about 75 wt. %, from about 25 wt. % to about 60 wt. % or from about 40 wt. % to about 60 wt. %

The composition may contain a binder. The binder may be any pharmaceutically acceptable binder. Specialists know the types of binders that are commonly used in this field of activity for the manufacture of pharmaceutical formulations. For example, the binder may be selected from gum arabic, agar, povidone, alginic acid, calcium alginate, calcium carbonate, calcium lactate, carbomer, calcium carboxyl methyl cellulose, sodium carboxyl methyl cellulose, carrageenan, microcrystalline cellulose, cellulose acetate phthalate, carob tree , chitosan, copovidone, corn starch, pre-gelatinized starch, crospovidone, cotton oil dextrates, dextrin, dextrose, ethyl cellulose, gelatin, glyceryl behenate, gua new gum, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydrogenated vegetable oil type I, hydroxypropyl starch, hypromellose, hypromellose acetate succinate, hypromellose phthalate, inulin, isomalt, lactose, liquid glucose, manulose nitrate, malite, magnesium molyte, molytol malate, malite, aluminum malt magnesium, malt poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, starch, stearic acid, sucrose, sunflower oil, tricaprilin, vit amine Ε polyethylene glycol succinate, xanthan gum and zein, or from any combination of these substances.

In one embodiment, the binder is selected from xanthan gum, hydroxypropyl methylcellulose, starch, sodium alginate, and povidone. Preferably, the binder is povidone.

The composition may contain any suitable amount of a binder. In a specific embodiment, the composition comprises from about 2 wt. % to about 15 wt. % binder. In other embodiments, the amount of binder in the composition may be from about 5 wt. % to about 12 wt. % or from about 6 wt. % to about 10 wt. %

In certain embodiments, the composition may contain a coloring agent. In addition, this coloring material can be dispersed in the composition so that the granules in cross section have a uniform color. This allows you to determine if the pellet production process has been carried out properly. For example, if the coloring material is not dispersed in the composition so that the granules in the cross section have a uniform color, this indicates that the manufacturing process was not carried out properly. This type of identification is relatively straightforward when compared to pellet tests. Thus, with any problems in the production process, they can be identified relatively easily and in the shortest possible time.

Also, all granules as a whole can have a uniform color, so that each granule individually has the same color as the rest. This, in turn, also allows you to quickly and easily evaluate the correctness of the production process. If not all granules are uniform in color, this indicates that the production process was not carried out properly.

Another advantage that all granules are uniform in color is that this makes the granules more aesthetically pleasing to the patient, in particular because in this case, the damaged (i.e., crushed) granules become less noticeable. This means that it may be easier for the patient to take the granules, and this helps the patient adhere to the treatment regimen and regimen.

Accordingly, in certain embodiments of the invention, the invention relates to a method for assessing the quality of a granule production process disclosed herein, which method includes evaluating the uniformity of the color distribution of the granules, the color of one single granule (in cross section) and / or the color distribution of all granules composition.

The uniformity of the color distribution of the granules (both the color of one single granule in cross section and the color distribution of all granules of the composition) can be measured using any method known to those skilled in the art. For example, color uniformity can be measured using colorimetric analysis.

For colorimetric measurements, a colorimeter can be used, for example, Jasco V-650 CFR with colorimetric analysis software. With the help of such equipment, it is possible to obtain measurement results in various color measurement systems:

- XYZ color space, a color model defined by the CIE (CIE, International Commission on Lighting) in 1931, where each XYZ symbol represents, respectively, red, green and blue; or

- color space CIE 1976 L * a * b *, where L * means lightness, a * indicates the color position in the range from magenta to green and b * indicates the color position in the range from yellow to blue, proposed by the CIE in 1976. This method is the preferred method for reporting results.

Using this equipment, L * a * b * values can be obtained from several samples of the same series. This allows you to determine the uniformity of the color of the samples.

There is also a USP test (USP) (<1061> COLOR-INSTRUMENTAL ANALYSIS METHODS. See USP 31, National Formulary 26, 2008, Rockville), which determines in detail the type of instrument and the degree of conversion between the above two color systems. This method is described in detail below:

The observed color of the object depends on the spectral energy of the radiation, the absorbing characteristics of the object and the sensitivity of the observer’s vision within the range of visibility. Similarly, it is important that these factors be considered when applying any instrumental method.

Any instrumental measurement of color is based on the fact that the human eye recognizes color through three “receptors”. Therefore, all colors can be represented as a combination of three color stimuli, suitably selected to stimulate all three receptors in the eye. Although there is no single set of natural light sources to match all colors (i.e., for any three selected light characteristics, some colors require a negative amount of one or more light characteristics), three conditional stimuli have been identified by which You can define all the real colors. Through large-scale experimental color matching studies involving people with normal color perception, distribution coefficients were measured for each wavelength of visible light (400 μm - 700 μm), and the relative stimulation amount of each receptor affected by radiation of the specified wavelength was obtained. These distribution coefficients x, y, z are shown below. Similarly, for any color, the amount of stimulation of each receptor in the eye is determined by the set of three color components of the light flux (Χ, Υ and Ζ) for that color.

The relationships between the distribution coefficient (see Figure 1) and the three color components are given in the equations:

Where

is the spectral intensity of the light sources and f _λ is either the spectral reflection coefficient (ρ _λ ) or the spectral transmittance (τ _λ ) of the material.

After three color components have been identified, they can be used to calculate color coordinates in an ideal three-dimensional color space, which is called a “visually uniform color space”. Many attempts have been made to define such a space, and many systems of color equations have been developed. The equations presented in this document represent a compromise between the simplicity of the calculations and the fit of the ideal model.

Color coordinates in a visually uniform color space can be used to calculate the color deviation from the selected control point. In the case when the instrumental method is used to determine the test result, when it is necessary to compare the color of the test preparation with the color of a standard or suitable liquid, the compared parameter is the difference, in a visually uniform color space, between the color of the control sample and the color of the test sample or standard.

PROCEDURE

In the spectrometric method, reflection or transmission values are obtained at a discrete wavelength over the entire spectrum of visible radiation using a bandwidth of 10 μm or less. These values are then used to calculate the three color components by using weighting factors (typical weighting factors are given in ASTM Ζ58.7.1-1951, according to the publication in the Journal of the American Optical Society, Volume 41, 1951, pp. 431-439). In the colorimetric method, weighing is carried out by using filters.

To measure the spectral reflection of opaque solids, the angle of view is separated from the angle of illumination so that only rays diffusely reflected from the test sample enter the receptor. Mirror reflection and ambient light are not taken into account.

To measure the spectral transmittance of transparent liquids, the sample is exposed to radiation at an angle of 5 degrees from the normal, and the transferred energy is measured exclusively within 5 degrees from the normal. The color of the solutions varies depending on the thickness of the measured layer. Except where other parameters should be used due to any special considerations, a 1 cm thick layer should be used. The methods described herein cannot be applied to turbid liquids or translucent solids.

CALIBRATION

For calibration purposes, one of the following reference materials may be used, in accordance with the instrument design. When measuring the transmittance, distilled water with a set transmittance of 1,000 at all wavelengths can be used as a white reference. Then, the values of the three color components Χ, Υ, and Ζ for the source of MCO C are 98.0, 100.0, and 118.1, respectively. Opaque ceramic plates can be used for measurement, the reference basis of which is a perfect diffuse reflector, the reflection characteristics of which are determined by the corresponding instrument device (Required equipment items can be purchased from BYK-Gardner, USA, 2431 Linden Lane, Silver Spring, state Maryland 20910 or from Hunter Associates Laboratory, Inc., 11491 Sunset Hills Road, Reston, VA 22090). If, due to any physical parameters of the sample, such plates cannot be used, sulfate-barium white reflectance standards may be used (suitable materials may be purchased from Eastman Kodak Company, Rochester, NY, 14650, “White reference standard”). After calibration with the above materials, it is advisable to make measurements as far as possible with reference material that is as close to the color as possible to the sample. If the test sample of the material is not suitable for use as a standard for a long time, color dies (Centroid Color Charts can be purchased from manufacturers of colorimeters) can be used, which cover the entire visually uniform color space with a fine gradation. The use of such a reference standard is recommended as a means of monitoring the instrument’s performance even for absolute color determination.

SPECTROPHOTOMETRIC METHOD

Reflectivity or transmittance in the range of 380-770 μm can be determined at intervals of 10 μm, and the results can be presented in percentage terms, the maximum value is 100.0. Then the three color components Χ, Υ and Ζ can be calculated as follows.

Reflective materials - For reflective materials, Χ, Υ and Ζ are defined as follows:

Where

- spectral transmittance of the material,

,

,

,

,

- known values for each reference source (typical weighting factors are given in accordance with the publication in the Journal of the American Optical Society, Volume 41, 1951, pages 431-439, and the required items of equipment can be purchased from ΒΥΚ-Gardner, USA, 2431 Linden Lane, Silver Spring, Maryland 20910 or from Hunter Associates Laboratory, Inc., 11491 Sunset Hills Road, Reston, Virginia 22090) and Δλ is expressed in μm.

Light-transmitting materials - For light-transmitting materials, the values of Χ, Υ and Ζ are calculated by the method described above, where τ _λ (spectral transmittance) is replaced by ρ _λ .

COLORIMETRIC METHOD

A suitable colorimeter can be used to obtain values equal to the three color components Χ, Υ, and Ζ (a colorimeter suitable for producing three color components can be obtained from BYK-Gardner, USA, 2431 Linden Lane, Silver Spring, Maryland 20910, or Hunter Associates Laboratory, Inc., 11491 Sunset Hills Road, Reston, VA 22090). The accuracy of the extent to which the measurement results obtained using the filter colorimeter correspond to the three color components can be shown by determining the three color components of the plates with highly saturated colors and by comparing these values with the values obtained by spectrometric measurements using a spectrophotometer.

Interpretation

COLOR COORDINATES

Color coordinates, L *, a * and b * are defined as follows:

where X _o , Y _o and Ζ _o are the three color components of a nominally white or colorless standard and Υ / Υ _o > 0.01. Usually they are equal to the three color components of a standard light source, with a Υ _o value of 100.0. In this case, X _o = 98.0 and Ζ _o = 118.1.

COLOR DIFFERENCE

Total color difference, ΔЕ *,

where ΔL *, Δ a * and Δb * mean the difference in color coordinates for the compared samples. Measurement results may be affected by instrumental variables.

The color of the granule or granules is considered to be uniform if the color difference (ΔЕ * (as defined above)) between two color coordinates having the most distant position in the color space when measuring at a specific location of the granule or granules is less than 2, 0. This means that there are slight variations in the color of the granules or granules, however, such variations may be weakly or completely indistinguishable to the human eye. Testing the color difference (ΔE *) can be carried out by the method described above, for example, using a test according to the method of the US Pharmacopoeia (USP) 1061. Preferably, the color difference (ΔE *) is less than about 1.9, 1.8, 1 , 7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6 or 0.5 .

A coloring material may be any pharmaceutically acceptable coloring material that will color the granules. Specialists know the types of coloring substances that are commonly used in this field of activity for the manufacture of pharmaceutical formulations. For example, the coloring matter may contain a pigment selected from calcium carbonate, iron oxides, dye varnishes, titanium oxide, caramel dyes, charming red AC dye, amaranth dye, anthocyanins, azorubine, beet red dye, canthaxanthin, carmine , D&C red 33 dye, eosin YS dye, erythrosine, ruby lithol, phloxin B, ponso 4P, Red 2G dye, beta-carotene, carotene pigments, curcumin, D&C yellow 10 dye, quinoline yellow WS dye, riboflavin, dye "yellow sunset FCF ”, tartrazine, chlorophylls and chlorophyllins, copper complexes of chlorophylls and chlorophyllins, dye“ green persistent FCF ”, dye“ green S ”, dye“ blue shiny FCF ”, indigotine, dye“ blue patented V ”, dye“ diamond black ΒΝ ”and vegetable coal or from combinations of these substances. In one embodiment, the colorant is a red colorant such as “Opadry 31K250002 red” or “AquaPolish D red”. The colorant may also contain a plasticizer, a binder, and, if necessary, a base material. A lubricant (s) may also be added to the colorant. For example, a plasticizer and / or a binder may facilitate the adherence of a coloring agent to excipients and / or to the outer surface of the granules to obtain granules with a uniform color and a uniform coating. Suitable plasticizers, binders, base materials and lubricants are known to those skilled in the art, but they can also be selected from the lists below.

The plasticizers can be selected from acetyl tributyl citrate, benzyl benzoate, chlorobutanol, dextrin, dibutyl phthalate, dibutyl sebacinate, diethyl phthalate, dimethyl phthalate, glycerol, glycerol monostearate, mannitol, polyethylene nitrolynolate polyinolate plynolino-olinolithin polyinolate polyinolate sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine and triethyl citrate, or a mixture of two or more of these substances.

Binders can be selected from carbomers, dextrin, hypromellose and a polymer of polyvinyl methyl ether with maleic anhydride or a mixture of two or more of these substances.

Substances of the base can be selected from acetyl triethyl citrate, calcium carbonate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, carnauba wax, cellulose acetate, phthalate cellulose acetate, ceresin, cetyl alcohol, chitosan, ethyl cellulose, glycerol, glycerol acetate, fructose gelate hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, isomalt, latex particles, glucose, lactose, maltitol, maltodextrin, methyl cellulose cellulose, microcrystalline wax, paraffin, poloxamer, polydextrose, polyethylene glycol, polyethylene oxide, poly-DL-lactic acid, polyvinyl acetate phthalate, polyvinyl alcohol, potassium chloride, povidone, shellac, starch and its derivatives, sucrose, titanium nitrate, titanium nitrate, tritium titrate , white wax, xylitol and yellow wax, or a mixture of two or more of these substances.

Lubricants can be selected from calcium stearate, colloidal silicon dioxide, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, leucine, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, magnesium myristic acid, palmitic acid, benzoic acid sodium polysulfate sodium, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil and zinc stearate or a mixture of two or more of these substances.

The composition may contain from about 1 wt. % to about 20 wt. % coloring matter. In certain embodiments, the amount of colorant in the composition may be from about 1 wt. % to about 15 wt. %, from about 1 wt. % to about 10 wt. % or from about 4 wt. % to about 8 wt. %

The composition may also contain a flavoring substance. The flavoring agent may be any pharmaceutically acceptable flavoring agent. Specialists are aware of the types of flavoring agents that are commonly used in the art for the manufacture of pharmaceutical formulations. For example, the flavoring agent may be selected from chocolate flavoring, flavorings used in the manufacture of chewing gum, coconut flavoring, coffee flavoring, fruit flavoring (such as wild cherry, strawberry, banana, grape, peach ”And“ raspberries ”), peppermint oil, curly mint oil, orange oil, peppermint flavor, anise flavor, honey flavor, vanilla flavor, tea flavor, verbena flavor and p various fruit acids, such as citric acid, ascorbic acid and tartaric acid, or from mixtures of these substances. The composition may contain from about 0.05 wt. % to about 5 wt. % flavoring substance.

The composition may also contain a sweetener. The sweetener may be any pharmaceutically acceptable sweetener. Specialists are aware of the types of sweeteners that are commonly used in the art for the manufacture of pharmaceutical formulations. For example, the sweetener may be selected from acesulfame potassium, aspartame, sucrose, sucralose, saccharin sodium, sugar, dextrose, fructose, mannitol, xylitol, alitam, glucose, lactitol, maltitol, maltose, sodium cyclamate, sorbitol, gluconate and cyclamate or from mixtures these substances. The composition may contain from about 0.1 wt. % to about 10 wt. % sweetener.

In a specific embodiment, the invention provides a solid pharmaceutical composition for oral administration comprising eslicarbazepine acetate and one or more pharmaceutically acceptable excipients, the composition being in the form of granules, and where at least 90% of the granules of the composition have a particle size of 90 microns or more, and / or where at least 50% of the granules of the composition have a particle size of 250 μm or more, and the composition contains from about 5 wt. % to about 15 wt. % eslicarbazepine acetate, from about 70 wt. % to about 80 wt. % filler, from about 2 wt. % to about 15 wt. % povidone, and from about 1 wt. % to about 10 wt. % of a coloring material, the filler containing lactose and disubstituted calcium phosphate dihydrate, the composition containing from about 40 wt. % to about 60 wt. % lactose and from about 15 wt. % to about 30 wt. % disubstituted calcium phosphate dihydrate, and moreover, the granules of the composition in cross section have a uniform color.

As will be appreciated by those skilled in the art, one or more pharmaceutically acceptable excipients may be any suitable excipients that are commonly used in the art for the manufacture of pharmaceutical formulations. For example, one or more pharmaceutically acceptable excipients may be any pharmaceutically acceptable carrier, adjuvant, or base material. Pharmaceutically acceptable carriers, adjuvants or base materials that can be used in the manufacture of the pharmaceutical compositions of the present invention are substances that are commonly used for the manufacture of pharmaceutical formulations and which include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, oxide aluminum, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffering agents such as phosphates, glycerin, sorbic acid potassium sorbate, partial mixtures of glyceride with saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon oxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene , sodium carboxylmethyl cellulose, polyacrylates, waxes, block copolymers of polyethylene and polyoxypropylene, polyethylene glycol and wool fat, or combinations thereof.

The pharmaceutical compositions of the present invention are preferably intended for oral use. In one embodiment, the composition may be used in combination with the food consumed by the patient, or the food may be sprinkled with the composition.

The composition of the present invention can be used with one or more additional active pharmaceutical ingredients, which can either be contained in the composition or used separately, either simultaneously or one substance after another.

In accordance with a second aspect, the present invention provides a method for producing a granular composition containing a pharmaceutically active substance, said method comprising the following steps:

(1) granulating a mixture containing a pharmaceutically active substance and one or more pharmaceutically acceptable excipients using a first granulating liquid;

(2) drying the granules formed in step (1);

(3) if necessary, calibrating the size of the granules obtained in step (2);

(4) granulating the granules obtained in step (2) or (3) using a second granulating liquid;

(5) drying the granules formed in step (4);

(6) coating the granules obtained in step (5) using a coating liquid; and

(7) drying the coated granules formed in step (6), wherein at least 90% of the obtained coated granules have a particle size of 90 μm or more, and / or at least 50% of the obtained coated granules have a particle size of 250 microns or more.

As understood by those skilled in the art, there are many different types of laboratory equipment suitable for granulating, drying granules and / or for coating granules. For example, items of equipment that are suitable for granulation include a high shear granulator, a fluid bed dryer, or a device where both of these items are combined into one system. Items of equipment that are suitable for drying granules include a fluidized bed dryer, a continuous fluidized bed, a device where both of these elements are combined into one system and a centrifugal dryer. Parts of equipment that are suitable for coating granules include a fluid bed dryer, a coating device, and a vertical centrifugal coating device. Specialists are aware of these types of equipment, the principles of their operation and various parameters used in the operation of such equipment.

In a high shear granulator, some parameters that can be changed to influence the granulation process are mixer speed, flow rate in the mixer, product temperature, crusher speed and flow rate in the crusher. In addition, the length of the time period for which a certain parameter is set, the value of which is set at a certain level, can vary, and various combinations of parameters, for example, various combinations of speed parameters, can be used. Those parameters are known to those skilled in the art, as well as methods for adjusting them in a granulator with high shear.

In a fluidized bed dryer, some parameters that can be changed in order to influence the granulation, drying and / or coating processes are the supply air temperature, the product temperature, the outlet air temperature, the drying flow rate (this parameter can also called “air flow rate”), pump speed, pressure in the pump and type of spray tip. In addition, the length of the time period for which a certain parameter is set, the value of which is set at a certain level, can be varied, and various combinations of parameters can be used, for example, various combinations of temperature parameters and / or air flow rates. Those parameters are known to those skilled in the art, as well as methods for adjusting them in a fluid bed dryer.

For clarity, some of the parameters mentioned below in the text of this document are given the following definitions:

"Supply air temperature" means the temperature of the air that enters the fluidized bed dryer. It is measured continuously throughout the process using a thermometer that is attached to the feed point in a fluidized bed dryer.

"Product temperature" (or "pellet temperature") means the temperature of the air, and therefore the temperature of the product (or pellets) inside the fluidized bed dryer. It is measured continuously throughout the process using a thermometer that is attached inside the fluidized bed dryer.

“Drying flow rate” or “flow rate” means the amount of air passing through a fluidized bed dryer per unit time — m ³ / cm ² / h. It is measured continuously using a flow meter located inside the device.

“Maximum flow rate” means the maximum flow rate that can be achieved in a dryer.

“Percentage of the total volume of a fluidized bed dryer per minute” is a measure of the rate at which a fluid, such as a granulating liquid, is fed to a fluidized bed dryer, which depends on the volume of the fluidized bed dryer. For example, a feed rate of 10% of the total volume of a fluidized bed dryer per minute corresponds to a feed rate of 5 L / min for a 50 L fluidized bed dryer and a feed rate of 100 L / min for a 1000 L fluidized bed dryer.

The mixture granulation of which is carried out in step (1) can be any suitable mixture containing a pharmaceutically active substance and one or more pharmaceutically acceptable excipients. The pharmaceutically active substance can be any pharmaceutically active substance with which it is desirable to produce relatively large granules. In one embodiment, the pharmaceutically active substance is eslicarbazepine acetate.

In one of the embodiments of the invention, the mixture contains from about 2 wt. % to about 98 wt. % pharmaceutically active substance, such as eslicarbazepine acetate. In some such embodiments, the mixture comprises at least about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15 wt. % pharmaceutically active substance, such as eslicarbazepine acetate. In some such embodiments, the mixture contains up to about 85%, 70%, 60%, 50%, 40%, 35%, 30%, 25%, 20% or 15 wt. % pharmaceutically active substance, such as eslicarbazepine acetate. In certain embodiments, the amount of pharmaceutically active substance in the mixture may be from about 5 wt. % to about 85 wt. %, from about 7 wt. % to about 70 wt. %, from about 10 wt. % to about 50 wt. %, from about 5 wt. % to about 25 wt. % or from about 5 wt. % to about 15 wt. %

The mixture may contain a filler. In one of the embodiments of the invention, the mixture contains from about 2 wt. % to about 98 wt. % filler. In some such embodiments, the mixture comprises at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75 wt. % filler. In some such embodiments, the mixture contains up to about 95%, 90%, 85%, 80%, or 75 wt. % filler. In certain embodiments of the invention, the amount of filler in the mixture is from about 15 wt. % to about 95 wt. %, from about 30 wt. % to about 90 wt. %, from about 50 wt. % to about 80 wt. %, from about 60 wt. % to about 90 wt. % or from about 70 wt. % to about 80 wt. %

The filler may be selected from one or more of the following materials: lactose, disubstituted calcium phosphate dihydrate, and isomalt. Preferably, the filler is lactose and disubstituted calcium phosphate dihydrate; or isomalt and disubstituted calcium phosphate dihydrate; or lactose and isomalt. More preferably, the filler is lactose and disubstituted calcium phosphate dihydrate.

When the filler contains lactose, the mixture preferably contains from about 5 wt. % to about 90 wt. % lactose. In certain embodiments of the invention, the mixture contains at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50 wt. % lactose. In certain embodiments, the mixture comprises up to about 85%, 80%, 75%, 70%, 65%, 60%, or 55 wt. % lactose. In certain embodiments, the amount of lactose in the mixture may be from about 5 wt. % to about 80 wt. %, from about 15 wt. % to about 75 wt. %, from about 25 wt. % to about 60 wt. % or from about 40 wt. % to about 60 wt. %

When the filler contains disubstituted calcium phosphate dihydrate, the mixture preferably contains from about 10 wt. % to about 50 wt. % disubstituted calcium phosphate dihydrate. More preferably, the amount of disubstituted calcium phosphate dihydrate in the mixture is from about 15 wt. % to about 50 wt. %, from about 10 wt. % to about 35 wt. %, from about 15 wt. % to about 30 wt. %, from about 15 wt. % to about 25 wt. % or from about 20 wt. % to about 25 wt. %

When the filler contains isomalt, the mixture preferably contains from about 5 wt. % to about 90 wt. % isomalt. In certain embodiments of the invention, the mixture contains at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50 wt. % isomalt. In certain embodiments, the mixture comprises up to about 85%, 80%, 75%, 70%, 65%, 60%, or 55 wt. % isomalt. In certain embodiments, the amount of isomalt in the mixture may be from about 5 wt. % to about 80 wt. %, from about 15 wt. % to about 75 wt. %, from about 25 wt. % to about 60 wt. % or from about 40 wt. % to about 60 wt. %

In some embodiments, the mixture that is granulated in step (1) also contains a binder. The binder may be any suitable binder. In some cases, the binder may be selected from xanthan gum, hydroxypropyl methylcellulose, starch, sodium alginate and povidone. In one embodiment, the binder is povidone.

In some embodiments, the first granulating liquid is an aqueous solution containing a binder. The binder may be selected from xanthan gum, hydroxypropyl methylcellulose, starch, sodium alginate and povidone. In one embodiment, the first granulating liquid is an aqueous solution containing povidone.

In some cases, the mixture that is granulated in step (1) also contains a coloring agent. In one embodiment of the invention, the first granulating liquid comprises a coloring material.

Often, the mixture may also contain a sweetener and / or flavoring agent. The first granulating liquid may also contain a sweetener and / or flavoring agent.

The mixture may also contain one or more additional active pharmaceutical ingredients.

The granulation in step (1) can occur using any suitable granulator. In some embodiments, the granulation is carried out in a high shear granulator or in a fluidized bed dryer. In one embodiment, the granulation is carried out in a high shear granulator. In yet another embodiment, the granulation is carried out in a fluidized bed dryer.

The first granulating liquid may be any suitable granulating liquid. In one embodiment, the first granulating liquid comprises water. Alternatively, the granulating liquid may contain alcohol, acetone or another organic solvent or combinations of these substances. As indicated above, the first granulating liquid may also be combined with a binder, coloring agent, sweetener and / or flavoring agent.

In one embodiment of the invention, the first granulating liquid is added before the granulation step. Alternatively, the first granulating liquid may be added during the granulation step. In a particular embodiment, the rate of addition of the first granulating liquid increases over time.

When a granulator with high shear is used in the granulation in step (1), the granulator speed can be from about 50 to about 500 rpm. According to other embodiments of the invention, the granulator speed may be from about 50 rpm to about 400 rpm, from about 100 rpm to about 400 rpm, from about 150 rpm to about 350 rpm, from about 100 rpm to about 300 rpm or about 150 rpm to about 250 rpm

When a granulator with a high shear force is used in the granulation in step (1), the crusher speed can be from about 50 to about 5000 rpm. According to other embodiments of the invention, the crusher speed may be from about 50 rpm to about 4000 rpm, from about 100 rpm to about 4000 rpm, from about 150 rpm to about 3,500 rpm or from about 200 rpm to about 3,000 rpm

In some preferred embodiments, when a granulator with high shear is used in the granulation in step (1), the crusher speed can be from about 50 to about 500 rpm. According to other embodiments of the invention, the crusher speed may be from about 50 rpm to about 450 rpm, from about 100 rpm to about 400 rpm, from about 150 rpm to about 350 rpm or from about 200 rpm to about 300 rpm

When a fluidized bed dryer is used in the granulation in step (1), the rate of addition of the first granulating liquid can be from about 0.02% to about 5% of the total volume of the fluidized bed dryer per minute. In other embodiments, the rate of addition of the first granulating liquid can be from about 0.02% to about 4%, from about 0.02% to about 3%, from about 0.02% to about 2%, or from about 0, 02% to about 1% of the total fluid bed dryer per minute. The rate of addition of the first granulating liquid can be controlled by the speed of the pump of the fluidized bed dryer.

When a fluidized bed dryer is used in the granulation in step (1), air is used to deliver the first granulating liquid to the fluidized bed dryer. The air pressure used to deliver the granulating liquid to the fluidized bed dryer can be from about 0.1 bar (10 kPa) to about 6 bar (600 kPa), from about 0.1 bar (10 kPa) to about 4 bar ( 400 kPa), from about 1 bar (100 kPa) to about 3 bar (300 kPa), from about 1.5 bar (150 kPa) to about 2.5 bar (250 kPa).

When a fluidized bed dryer is used in the granulation in step (1), the air flow during granulation can be from about 10% to about 100% of the maximum flow rate of the fluidized bed dryer. In other embodiments, the granulation air flow rate may be from about 20% to about 95%, from about 30% to about 90%, or from about 40% to about 90%, or from about 70% to about 80% of the maximum speed fluidized bed dryer.

In certain embodiments of the invention, when a fluidized bed dryer is used in the granulation in step (1), the air flow rate in the granulation can be from about 20% to about 80%, from about 30% to about 70%, or from about 40% to about 60% of the maximum flow rate of a fluidized bed dryer.

In one embodiment of the invention, the air flow during the granulation increases stepwise over time.

When a fluidized bed dryer is used in the granulation in step (1), the temperature of the granulated air dryer supplied to the fluidized bed dryer can be from about 30 ° C to about 80 ° C, from about 50 ° C to about 80 ° C, or from about 60 ° C to about 80 ° C.

The temperature of the mixture during granulation in step (1) can be from about 10 ° C to about 70 ° C. In other embodiments, the temperature of the granulation mixture in step (1) may be from about 20 ° C to about 60 ° C, from about 25 ° C to about 50 ° C, or from about 30 ° C to about 50 ° C.

Drying in step (2) can occur using any suitable dryer. In one embodiment of the invention, the drying is carried out in a fluidized bed dryer. Drying can continue until the relative humidity of the granules reaches about 6% or less, about 5% or less, about 4% or less, or about 3% or less. The relative humidity of the granules can be determined using a moisture balance or a moisture analyzer.

When a fluidized bed dryer is used in the drying in step (2), drying of the granules can take place at a supply air temperature and a temperature of granules (product) of from about 40 ° C to about 80 ° C or from about 50 ° C to about 80 ° C . Also, the drying of the granules can occur at a drying flow rate of from about 20% to about 90% of the maximum flow rate of a fluidized bed dryer or from about 20% to about 75% of the maximum flow rate of a fluidized bed dryer.

In certain embodiments of the invention, when a fluidized bed dryer is used in the drying in step (2), drying of the granules can occur at a supply air temperature and a temperature of granules (product) of from about 50 ° C to about 80 ° C or from about 60 ° C to about 80 ° C. Drying of the granules can occur at a drying flow rate of from about 20% to about 50% of the maximum flow rate of the fluidized bed dryer.

Calibration in step (3) can be applied so that the granules obtained in step (2) have a suitable size for granulation in step (4). If necessary, this may include removing granules that are larger than a certain size, or reducing their size. In fact, the calibration step ensures that the size of all the granules does not exceed a certain value. This can be done in any suitable way, for example, using sieves or several sieves. According to some embodiments of the invention, using a vibrating sieve or several vibrating sieves, it is possible to break up the granules into smaller ones so that they pass through the openings of the sieve. The calibration may include a step where the granules obtained in step (2) are sieved through a sieve so that the granules have a particle size of about 2 mm or less, about 1.5 mm or less, or about 0.8 mm or less.

The granulation in step (4) may occur using any suitable granulator. In one embodiment of the invention, the granulation is carried out in a fluidized bed dryer.

In some embodiments, granulation of the granules in step (4) occurs using a binder. The binder may be any suitable binder. In some cases, the binder may be selected from xanthan gum, hydroxypropyl methylcellulose, starch, sodium alginate and povidone. In one embodiment, the binder is povidone.

In some embodiments, the second granulating liquid is an aqueous solution containing a binder. The binder may be selected from xanthan gum, hydroxypropyl methylcellulose, starch, sodium alginate and povidone. In one embodiment, the second granulating liquid is an aqueous solution containing povidone.

In some cases, granulation of the granules in step (4) occurs using a coloring agent. In one embodiment of the invention, the second granulating liquid is combined with a coloring material.

The second granulating liquid may be any suitable granulating liquid. In one embodiment, the second granulating liquid comprises water. Alternatively, the granulating liquid may contain alcohol, acetone or another organic solvent or a combination of these substances.

In one embodiment of the invention, a second granulating liquid is added prior to the granulation step. Alternatively, a second granulating liquid may be added during the granulation step. In a particular embodiment, the rate of addition of the second granulating liquid increases over time.

When a fluidized bed dryer is used in the granulation in step (4), the rate of addition of the second granulating liquid can be from about 0.02% to about 5% of the total volume of the fluidized bed dryer per minute. In other embodiments, the rate of addition of the second granulating liquid can be from about 0.02% to about 4%, from about 0.02% to about 3%, from about 0.02% to about 2%, or from about 0, 02% to about 1% of the total fluid bed dryer per minute. The rate of addition of the second granulating liquid can be controlled by the speed of the pump of the fluidized bed dryer.

When a fluidized bed dryer is used in the granulation in step (4), air is used to deliver the second granulating liquid to the fluidized bed dryer. The air pressure used to deliver the granulating liquid to the fluidized bed dryer can be from about 0.1 bar (10 kPa) to about 6 bar (600 kPa), from about 0.1 bar (10 kPa) to about 4 bar ( 400 kPa), from about 1 bar (100 kPa) to about 3 bar (300 kPa), from about 1.5 bar (150 kPa) to about 2.5 bar (250 kPa).

When a fluidized bed dryer is used in the granulation in step (4), the air flow rate in the granulation can be from about 10% to about 100% of the maximum flow rate of the fluidized bed dryer. In other embodiments, the granulation air flow rate may be from about 20% to about 95%, from about 30% to about 90%, or from about 40% to about 90% of the maximum flow rate of a fluidized bed dryer.

In certain embodiments of the invention, when a fluidized bed dryer is used in the granulation in step (4), the air flow during granulation can be from about 20% to about 80%, from about 30% to about 70%, or from about 40% to about 60% of the maximum flow rate of a fluidized bed dryer.

In one embodiment of the invention, the air flow during the granulation increases stepwise over time.

When a fluidized bed dryer is used in the granulation in step (4), the temperature of the granulated air dryer supplied to the fluidized bed dryer can be from about 30 ° C to about 80 ° C, from about 50 ° C to about 80 ° C, or from about 60 ° C to about 80 ° C.

The granule temperature during granulation in step (4) can be from about 10 ° C to about 70 ° C. In other embodiments, the temperature of the granules during granulation in step (4) can be from about 20 ° C to about 60 ° C, from about 25 ° C to about 50 ° C, or from about 30 ° C to about 50 ° C.

Drying in step (5) may occur using any suitable dryer. In one embodiment of the invention, the drying is carried out in a fluidized bed dryer. Drying can continue until the relative humidity of the granules reaches about 5% or less, about 4% or less, or about 3% or less.

When a fluidized bed dryer is used in the drying in step (5), drying of the granules can take place at a supply air temperature and a temperature of granules (product) of from about 40 ° C to about 80 ° C or from about 50 ° C to about 80 ° C . Also, granule drying can occur at a drying flow rate of from about 20% to about 90% of the maximum flow rate of a fluidized bed dryer or from about 20% to about 75% of the maximum flow rate of a fluidized bed dryer.

In certain embodiments of the invention, when a fluidized bed dryer is used during drying in step (5), drying of the granules can occur at a supply air temperature and a temperature of granules (product) of from about 50 ° C to about 80 ° C or from about 60 ° C to about 80 ° C. Drying of the granules can occur at a drying flow rate of from about 20% to about 50% of the maximum flow rate of the fluidized bed dryer.

The coating in step (6) may occur using any suitable coating equipment. In one embodiment of the invention, the coating is carried out in a fluidized bed dryer.

The coating fluid may be any suitable fluid containing components for coating the granules. In one embodiment, the coating fluid is an aqueous solution. Alternatively, the coating liquid may contain alcohol, acetone, or another organic solvent, or combinations of these substances.

When a fluidized bed dryer is used in step (6), the rate of addition of the coating fluid may be from about 0.02% to about 5% of the total volume of the fluidized bed dryer per minute. In other embodiments, the rate of addition of the coating liquid may be from about 0.02% to about 4%, from about 0.02% to about 3%, from about 0.02% to about 2%, or from about 0 , 02% to about 1% of the total volume of the fluidized bed dryer per minute.

When a fluidized bed dryer is used in the implementation of step (6), air is used to deliver the coating fluid to the fluidized bed dryer. The air pressure used to deliver the coating fluid to the fluidized bed dryer may be from about 0.1 bar (10 kPa) to about 6 bar (600 kPa).

When a fluidized bed dryer is used in step (6), the temperature of the air supplied to the fluidized bed dryer during coating is from about 30 ° C to about 80 ° C.

The temperature of the granules in step (6) may be from about 10 ° C to about 70 ° C. In other embodiments, the temperature of the granules may be from about 20 ° C to about 60 ° C, from about 25 ° C to about 50 ° C, or from about 30 ° C to about 50 ° C.

In some embodiments of the invention, the coating of the granules in step (6) occurs using a coloring agent. In one embodiment, the coating fluid comprises a coloring agent. When the coating liquid contains a coloring liquid, the coating of the granules can be carried out so that any unpleasant odor, for example, due to the taste of excipients or the taste of eslicarbazepine acetate, is not noticeable until the patient swallows the granules .

Drying in step (7) may occur using any suitable dryer. In one embodiment of the invention, the drying is carried out in a fluidized bed dryer. Drying can continue until the relative humidity of the granules reaches about 5% or less, about 4% or less, or about 3% or less.

When a fluidized bed dryer is used in the drying in step (7), drying of the granules can occur at a supply air temperature and a temperature of granules (product) of from about 40 ° C to about 80 ° C or from about 50 ° C to about 80 ° C . Also, granule drying can occur at a drying flow rate of from about 20% to about 90% of the maximum flow rate of a fluidized bed dryer or from about 20% to about 75% of the maximum flow rate of a fluidized bed dryer.

In certain embodiments of the invention, when a fluidized bed dryer is used during drying in step (7), drying of the granules can occur at a supply air temperature and a temperature of granules (product) of from about 50 ° C to about 80 ° C or from about 60 ° C to about 80 ° C. Drying of the granules can occur at a drying flow rate of from about 20% to about 50% of the maximum flow rate of the fluidized bed dryer.

The specialist will understand that, despite the fact that steps (1) and (2), (4) and (5) and (6) and (7) are presented here as separate steps, if these steps are carried out using one device or item of equipment, then they can occur at the same time, or when these steps are performed, the next stage can begin before the previous one has ended. For example, granulation can be carried out while the granules are dried. A short granulation step may be carried out, followed by a granulation and drying step, followed by a drying step. Thus, some parameters related to granulation can also relate to drying and vice versa.

In accordance with another aspect, the invention provides a composition that can be obtained using the process described above, and / or a composition produced using the process described above.

Since the process described above can be used to produce the compositions described in the first aspect of the invention, one skilled in the art will appreciate that any limitations described for these compositions also apply to the process, for example, restrictions regarding the size of granules produced by process, as well as quantities of excipients, filler and binders.

In accordance with another aspect, the invention provides any of the compositions described above, intended for use for therapeutic purposes

In accordance with another aspect, the invention provides any of the compositions described above, wherein the pharmaceutically active substance is eslicarbazepine acetate, for the treatment or prophylaxis of diseases selected from epilepsy, neuropathic pain, migraine, fibromyalgia, and affective disorders.

The invention also provides the use of any of the compositions described above, wherein the pharmaceutically active substance is eslicarbazepine acetate, for the manufacture of a medicament for the treatment or prevention of diseases selected from epilepsy, neuropathic pain, migraine, fibromyalgia and affective disorders.

In some embodiments, the neuropathic pain is selected from trigeminal neuralgia, phantom pain, diabetic neuropathy, and postherpetic neuralgia.

In some embodiments, the affective disorder is selected from bipolar disorder, depression, premenstrual dysphoric disorder, postpartum depression, postmenopausal depression, anorexia nervosa, bulimia nervosa, or depressive symptoms associated with neurodegenerative diseases, unstable fast bipolar disorder (fast) manic-depressive disorder, acute manic state, solitary mood disorder, ma niacal episode and episode of hypomania.

The invention also provides a method of treating or preventing a disease, comprising administering to a patient in need of such treatment an effective amount of a composition as described above, wherein the pharmaceutically active substance is eslicarbazepine acetate, the disease selected from epilepsy, neuropathic pain, migraine, fibromyalgia and affective disorders.

In one embodiment, the patient is a human.

The use of the compositions may be carried out with another active pharmaceutical ingredient (s). Such combination therapy includes the simultaneous or alternate use of the composition of the invention with other active pharmaceutical ingredients.

Description of Shapes

Figure 1 shows the relationship between a distribution coefficient and three color components for determining color.

The Figure 2 shows the distribution of granules by size in trial runs with APIs of Table 3.

Figure 3 shows the size distribution of granules for two batches according to this invention (Series 18 and 19) compared with the distribution of granule sizes (Series 20), which can typically be used in the manufacture of tablets.

Figure 4 shows equipment for measuring the apparent volume of a granular composition.

Figure 5 shows the physical dimensions (in cm) of a funnel for measuring the flow rate of a granular composition.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in more detail by way of example. The following examples are not intended to limit the scope of the present invention.

Example 1 - Procedure for the preparation of granules

EXPERIMENTAL PART

EQUIPMENT

Preparation of the drug was carried out using the following equipment:

- Mettler Toledo scales model PM 1200, code 5006;

- scales AND GX-1000, code 5033;

- mixer Ika RW20, code 5002;

- Erweka laboratory vibratory granulator FGS type with 1.6 mm screen connected to an Erweka rotor, type KU1, code 5007;

- laboratory V-shaped mixer connected to the Erweka rotor, type AR402, code 5015;

- Hearson dryer;

- two-cone mixer Silase, 50 l, code 5031;

- mixer / granulator Diosna P-VAC 60, code 5026; and

- fluid bed dryer Diosna САР 50, code 5025.

Testing of samples was carried out using the following equipment:

- Mettler Toledo scales, model AG 245, code 4122;

- a set of vibrating screens, code 4008;

- a Varian VK7025 dissolution apparatus connected to a Cary 50 UV-Vis spectrometer for optical spectroscopy of tablets via a Varian VK800 peristaltic pump, code 5024;

- Waters Alliance HPLC system, model 2695, with a diode array detector, model 2996, code 4040; and

- Waters Alliance HPLC system, model 2695, with diode array detector, model 2996, code 5020.

PARAMETERS AND METHODS

TRIAL SERIES

The preparation of the series was carried out using one of the following procedures:

- Procedure 1:

1. Mix the components in a fluid bed dryer;

2. Add granulating liquid and granulate;

3. Dry until the moisture content of the granules is less than 3%.

- Procedure 2:

1. Mix eslicarbazepine acetate and basic excipient in a double cone mixer;

2. Place the mixture in a fluidized bed dryer;

3. Add granulating liquid (with saccharin) and granulate;

4. Dry until the moisture content of the granules is less than 3%;

5. Repeat steps 3 and 4 (second granulation);

6. Add coating solution (with flavor);

7. Dry until the moisture content of the granules is less than 3%.

- Procedure 3:

1. Mix eslicarbazepine acetate and basic excipient in a Diosna mixer / granulator;

2. Add granulating liquid and granulate;

3. Place the mixture in a fluid-bed dryer and dry until the moisture content of the granules is less than 3%;

4. Add granulating liquid and granulate;

5. Dry until the moisture content of the granules is less than 3%;

6. Add coating solution;

7. Dry until the moisture content of the granules is less than 3%.

ANALYSIS OF GRANULOMETRIC COMPOSITION

The analysis of particle size distribution was carried out using a set of sieves in accordance with the procedure of the US Pharmacopoeia USP <786 - Determination of particle size distribution by analytical sieving>. See USP 31, National Formulary 26, 2008, Rockville.

ANALYSIS OF THE CONTENT OF API IN GRANULES AND ANALYSIS OF SOLUBILITY

The analysis of the content of eslicarbazepine acetate was carried out by HPLC, and satisfactory results were obtained for all series, i.e., the API content was 95-105%. In some embodiments of the invention, in the compositions of serial samples, the content of the main component according to the analysis results was at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98 % or 99%. Solubility analysis was performed using a rotary stirrer at 75 rpm and 100 rpm, and quantitative analysis was performed by HPLC (see <711 — Solubility>. See USP 31, National Formula 26, 2008, Rockville). Satisfactory results were obtained for all batches, i.e., solubility was ≥85% after 45 minutes. In some embodiments, the solubility in the serial sample compositions is at least about 50%, 60%, 70%, 80%, 85%, 90%, or 95%.

Color uniformity was evaluated visually.

RAW MATERIALS

SERIES

DATA ASSESSMENT

TRIAL SERIES

Based on the results shown in table 3, in all series the required particle size distribution was obtained. Series containing Emcompress® and galenIQ® 800 represent higher d10 and d90 values.

Based on the results of the analysis of the distribution of granule sizes shown in Figure 2, we can conclude that not all granules have the same properties. A granulate with a significantly smaller particle size was obtained in Series 1, which is the only series where only lactose was used as the main excipient.

In Series 5, Series 6, Series 7 and Series 8, the size distribution of the granules is highly variable, which may result from the wetting of the material before granulation.

A granulate with a noticeably larger particle size was obtained in Series 12, which is the only series where only galenIQ® 800 was used as the main excipient.

In all other series, the size distribution of granules was similar.

Based on the results shown in table 4, we can conclude that:

- by changing the procedure for adding a coating substance, various results can be obtained regarding the uniformity of color of the granules: in the case when the coating substance was divided into three parts, which were added at two stages of granulation and at the stage of coating, granules with improved color uniformity compared to the case when all the coating agent was added at a time in the last coating step;

- by changing the air supply rate and the speed of the liquid pump (instead of continuous - a phased increase), granules with an improved composition were obtained (Series 3 compared to Series 4);

- when adding granulating liquid to the granulation stage (initial pump speed), the content of the main component increased (Series 3 compared to Series 5; Series 4 compared to Series 6);

- when using a granulator with high shear at the granulation stage 1, the content of the main component significantly increased (Series 6 compared to Series 7);

- by increasing the amount of granulating liquid added prior to the granulation step, an improved content of the main component was obtained, however, the size distribution of the granules became less uniform;

- by increasing the amount of lactose in the preparation, improved solubility was obtained (Series 7 compared to Series 10 and Series 11);

- when using galenIQ® 800 instead of lactose, delayed solubility was obtained, however, granules of a larger size were also obtained;

- by increasing the dissolution rate of the main component, an improved dissolution rate of the preparation containing galenIQ® 800 was obtained;

- in the series where Opadry® 31K was used, better coloring and better uniformity of color were obtained compared to the series where Opadry® 03B was used (Series 15 compared to Series 16);

- calibration of the dried granules after granulation step 1 led to a more uniform distribution of granules in size (based on visual observations) (Series 14);

- by lowering the supply air temperature during the entire process, improved granule coloration was achieved in terms of its saturation and uniformity (Series 14).

findings

Of all the tested formulation variants, the best results were obtained when testing the formulation corresponding to series 14. This option provides a uniform granule size that meets the requirements, as well as a satisfactory content of the main component and a solubility profile. During the granulation step 2, the product temperature should be 34-36 ° C, and the coating on the product should be about 38 ° C, as this ensures that the granules do not adhere to the walls of the fluidized bed dryer, and this achieves an improved uniformity of the granules.

In order to obtain improved color uniformity, the coating agent is preferably divided into parts and added in the granulation step and the coating step.

BIBLIOGRAPHY

- Pharmaceutical Excipients Guide, 4th Edition, American Pharmaceutical Association, 2003

- European Pharmacopoeia, 6th edition, 2008, Strasbourg

- USP 31, National Formulary 26, 2008, Rockville

GENERALIZED RESULTS

In order to evaluate which excipients are most suitable, preliminary studies of the properties of the substances were carried out. After that, the selected excipients were used to obtain granules containing eslicarbazepine acetate under experimental conditions.

Fillers used in preliminary studies of the properties of substances were: Avicel® PH102, Emcompress®, Lactose 200M, GaleniQ® 800, Lactose 80M. They were used in combination with binders (sodium alginate, Starch 1500, xanthan gum, hydroxypropyl methylcellulose, PEG 6000, Povidone K-30, Eudragit® RL PO). Based on the obtained particle sizes (the larger, the better), trial series were selected containing lactose (200M and 80M), Emcompress® and GalenIQ® as the main auxiliary substance, and, as a binder, xanthan gum, hydroxypropyl methylcellulose, alginate sodium and povidone K-30. The use of these excipients with eslicarbazepine acetate was tested, and the resulting particle sizes met the relevant requirements.

Lactose 200M, Emcompress® and GalenIQ® 800/801 were used as the main excipients. Povidone K-30 was used as a binder. We also tested Opadry dyes of several colors / shades, as well as parameters that change when these dyes are added. We also tested the use of a high shear mixer in the first stage. The following parameters were examined:

Granulation stage 1 - granulator speed; crusher speed; granulating liquid; granulating liquid composition; drying flow rate; drying temperature;

Granulation step 2 — flow rate; initial speed of the pump; granulating liquid composition; spray pressure; supply air temperature; pump speed and pump frequency; drying flow rate; drying temperature;

The coating step is the flow rate; spray pressure; supply air temperature; pump speed; drying flow rate; drying temperature.

The following conclusions were made:

- an increase in the amount of coating agent does not improve color uniformity;

- by changing the procedure for adding a coating substance, various results can be obtained regarding the uniformity of color of the granules: in the case when the coating substance was divided into three parts, which were added at two stages of granulation and at the stage of coating, granules with improved color uniformity compared to the case when all the coating agent was added at a time in the last coating step;

- by changing the air supply rate and the speed of the liquid pump (instead of continuous - a phased increase), granules with an improved composition were obtained;

- when adding granulating liquid to the granulation stage (initial pump speed), the content of the main component increased;

- when using a granulator with high shear at the granulation stage 1, the content of the main component significantly increased;

- by increasing the amount of granulating liquid added prior to the granulation step, an improved content of the main component was obtained, however, the size distribution of the granules became less uniform;

- as a result of adding baking powder to the preparation, a significant improvement in solubility did not occur:

- by increasing the amount of lactose in the preparation, improved solubility was obtained;

- when using galenIQ® 800/801 instead of lactose, delayed solubility was obtained, however, granules of a larger size were also obtained;

- by increasing the dissolution rate of the main component and the rotation speed of the mixer, an improved dissolution rate of the preparation containing galenIQ® 800 was obtained;

Example 2 - Comparison of the sizes of granules according to the invention with the sizes of pellets

Series 18 and Series 19 are granular compositions produced according to the present invention. Series 20 is a typical pellet size distribution that can be used in tablet manufacturing.

Figure 3 shows a graphical representation of the size distribution of granules.

Example 3 - Additional Data Relating to Comparison of the Properties of the Granules of the Invention and Tableted Granules

A laboratory scale series of 700 sachets was produced using the same oral granule manufacturing technology as described above (Series 19).

The manufacturing process for granulating tablets:

1 - mix povidone with distilled water until complete dissolution is achieved, then add saccharin and a part of Opadry, and then mix until a homogeneous suspension (granulating liquid) is obtained;

2 - mix the remaining components in a laboratory mixer / granulator;

3 - add granulating liquid and granulate to the laboratory mixer / granulator; and

4 - dry the granules in a fluidized bed dryer.

This series (Series 21) was then compared with the series obtained using the process of the invention (Series 19). The following results were obtained:

Based on the analysis of the results, the appearance of these two series was completely different. Series 19 was visually perceived as homogeneous granules having a red color, while Series 21 was visually perceived as granules and powder, which, depending on the particle, had a color from white to red.

In terms of density, Hausner index and Carr index, no significant differences between the series were found. Flow rate and angle of repose are better in Series 19, which shows that its fluidity is improved compared to pelletized pellets.

The particle size distribution in these two series was completely different. In Series 19, a narrower particle size distribution interval was obtained (the difference between the extreme values is 480.5 μm) compared to Series 21 (the difference between the extreme values is 1360.4 μm). As mentioned above, Series 19 was visually perceived as granules, and Series 21 was visually perceived as a mixture of granules of various sizes and powder.

Summing up, we can conclude that some of the advantages of the series produced by the process according to the invention (Series 19) compared to the series produced by the process of conventional granulation of tablets (Series 21) are:

- production of granules of uniform color;

- a narrower range of particle size distribution;

- improved fluidity.

Experiment Logs

The protocols for measuring solubility, fluidity, and apparent volume of granules are described below.

Visible Volume Measurement Protocols

EQUIPMENT (SEE FIGURE 4)

- Erweka SVW

- a 250 ml laboratory beaker with a graduation of 2 ml

PROCEDURE

It is necessary to carry out the following procedure in three parallel tests using the equipment shown in Figure 4:

1. Turn on the Erweka SVW equipment.

2. Weigh the sample, weighing about 100 g, write down the obtained value (Determination of apparent volume) and place the sample in a laboratory beaker using a funnel. If it is impossible to place a sample weighing 100 g in a beaker, select a sample with a visible volume of 50-250 ml and record the resulting mass.

3. Measure the initial volume (V ₀ - total volume, in ml) and write down the obtained value.

4. Set the programmed beat value to the Erweka SVW - 10 and press the START button.

5. Measure the volume after 10 strokes (Y ₁₀ , in ml) and record the value obtained.

6. Press the reset button, set the programmed beat value to Erweka SVW - 490 and press the START button.

7. Measure the volume after 500 strokes (V ₅₀₀ , in ml) and record the value obtained.

8. Press the reset button, set the programmed beat value to the Erweka SVW - 750 and press the START button.

9. Measure the volume after 1250 strokes (V ₁₂₅₀ is the volume of the shake, in ml) and write down the obtained value.

10. If the difference between the values of V ₅₀₀ and V _{1250 is} more than 2 ml, perform another 1250 strokes and write down the obtained value (V ₂₅₀₀ is the volume of the shake, in ml).

CALCULATIONS

From the results obtained earlier, make the following calculations:

D ₀ - Apparent Density

D ₁₀ - Density after 10 strokes

D ₅₀₀ - Density after 500 strokes

D ₁₂₅₀ - Bulk density

D ₂₅₀₀ - Bulk Density

Flow Measurement Protocols

EQUIPMENT

- System Pharma Test ^TM - PTG

- A funnel with the physical dimensions indicated in Figure 5 in cm.

- Tripod for funnel

- A sheet of graph paper

- Chronometer

- vernier caliper

DEFINITION USING THE PHARMA TEST SYSTEM

1. Turn on the Pharma ^TestTM - PTG system and select program 1.

2. Place a funnel in the device.

3. Weigh the 100 g sample, record the weight obtained and place it in the funnel. If a 100 g sample is larger than the funnel, weigh a smaller sample and record the weight.

4. Click “START”:

5. Record the travel time (t) in seconds and the angle of repose (α) in degrees (°).

6. Replace the powder in the funnel and repeat the procedure two more times. Calculate the average values of weight, travel time and angle of repose and write them down.

DETERMINATION BY THE METHOD USING A CROWN, WHICH IS DESCRIBED IN THE EUROPEAN PHARMACOPEIA

It is necessary to carry out the procedure described below in three parallel tests:

1. Place the funnel in a tripod at a height of 7 cm.

2. Place a sheet of graph paper or another device under the funnel that can correctly determine the area of the base of the powder cone that subsequently forms (for example, a Petri dish at the top of the beaker).

3. Place a 100 g sample in the funnel and close the powder outlet. Record the weight of the sample. If a 100 g sample is larger than the funnel, weigh a smaller sample and record the weight.

4. Open the powder outlet, whereupon the powder should spill out on graph paper. Record the time (t) during which the powder spilled out of the funnel in seconds (sec.).

5. A powder cone should form, outline the area of the base of the powder cone with a pen and measure its diameter (d) in cm. Record the obtained value.

6. Measure the height of the cone in cm using a vernier caliper and record the value obtained.

7. From the previously obtained results, calculate the flow velocity and angle of repose using the following formulas:

- h is the height of the cone;

- r is the radius of the base of the cone (d / 2).

8. Repeat the previous steps two times, calculate the average values and write them down.

Protocol for measuring the solubility of eslicarbazepine acetate contained in the composition

PROCEDURE

Rotary stirrer (apparatus 2; European Pharmacopoeia, section 2.9.3 and chapter <711> US Pharmacopoeia)

- Dissolution medium HCl 0.01 mol / L - Volume 1000 ml (± 1%) - Temperature 37.0 ± 0.5 ° C - Speed of the device for mixing 100 ± 4 rpm - test duration 30 minutes

INSTRUMENTAL TECHNIQUES

Reverse Phase High Performance Liquid Chromatography - UV Detection

Eluent A highly purified water obtained at MilliQPlus, filtered through a 0.45 μm membrane Eluent B acetonitrile, qualifications "for HPLC" Speaker Merck chromolith RP-18e, 100-4.6 mm or equivalent Flow rate 1.0 ml / min Detection 250 μm Sample Volume 20 μl Column temperature 30 ° C Mobile phase isocrate method; eluent A / eluent B (70:30) (v / v)

Example 4 - Stability of granular compositions

The stability test of the granular compositions of the present invention was tested.

The stability of Series 18 and 19 described above was tested when the granules were inside the sachet and also when the granules were not inside the sachet. Testing of the sachets was carried out at a temperature of 25 ° C and a relative humidity of 60%, and the duration of testing was 0, 3, 6, 9 and 12 months. Sachet was also tested at a temperature of 40 ° C and a relative humidity of 75%, and the testing duration was 0, 3, and 6 months. Satisfactory stability of the granules was demonstrated in terms of their light stability, impurity levels and API content.

Example 5 - Color uniformity of granular compositions

When the granules contain a colorant, this colorant can be dispersed in the composition so that the granules in cross section have a uniform color.

This uniform coloration makes it possible to determine whether the pellet production process was carried out properly. Thus, with any problems in the production process, they can be identified relatively easily and in the shortest possible time.

Also, all granules as a whole can have a uniform color, so that each granule individually has the same color as the rest.

Such uniform coloring, in turn, also makes it possible to quickly and easily evaluate the correctness of the production process. If not all granules are uniform in color, this indicates that the production process was not carried out properly.

It was shown that when the various granules of the composition have a uniform color, this makes the granules more aesthetically attractive to the patient, and it is also an empirical tool for assessing the quality of the product. This means that it may be easier for the patient to take the granules, and this helps the patient adhere to the treatment regimen and regimen.

Claims (76)

1. A solid pharmaceutical composition comprising eslicarbazepine acetate and one or more pharmaceutically acceptable excipients, characterized in that the composition is in the form of granules, where at least 90% of the granules of the composition have a particle size of 1200 μm or less, and that at least 90% of the granules of the composition have a particle size of 90 microns or more, and / or the fact that at least 50% of the granules of the composition have a particle size of 250 microns or more, where the particle size of these granules is determined by sieving. 2. The composition according to p. 1, characterized in that at least 90% of the granules of the composition have a particle size of 150 microns or more. 3. The composition according to p. 1, characterized in that at least 90% of the granules of the composition have a particle size of 200 μm or more. 4. The composition according to p. 1, characterized in that at least 50% of the granules of the composition have a particle size of 300 μm or more. 5. The composition according to p. 1, characterized in that at least 50% of the granules of the composition have a particle size of 400 microns or more. 6. The composition according to p. 1, characterized in that at least 90% of the granules of the composition have a particle size of 800 microns or less. 7. The composition according to p. 1, characterized in that at least 90% of the granules of the composition have a particle size of 500 μm or less. 8. The composition according to p. 1, characterized in that at least 90% of the granules of the composition have a particle size of 250 microns or more, and at least 90% of the granules of the composition have a particle size of 550 microns or less. 9. The composition according to p. 1, characterized in that at least 80% of the granules of the composition have a particle size in the range of 1000 microns. 10. The composition according to p. 1, characterized in that at least 80% of the granules of the composition have a particle size in the range of 600 μm. 11. The composition according to p. 1, characterized in that at least 80% of the granules of the composition have a particle size in the range of 300 microns. 12. The composition according to p. 1, characterized in that at least 80% of the granules of the composition have a particle size in the range of 200 μm. 13. The composition according to p. 1, containing from about 5 wt. % to about 85 wt. % eslicarbazepine acetate. 14. The composition according to p. 1, containing from about 7 wt. % to about 70 wt. % eslicarbazepine acetate. 15. The composition according to p. 1, containing from about 10 wt. % to about 50 wt. % eslicarbazepine acetate. 16. The composition according to p. 1, containing from about 5 wt. % to about 15 wt. % eslicarbazepine acetate. 17. The composition according to p. 1, containing from about 15 wt. % to about 95 wt. % filler. 18. The composition according to p. 1, containing from about 30 wt. % to about 90 wt. % filler. 19. The composition according to p. 1, containing from about 50 wt. % to about 80 wt. % filler. 20. The composition according to p. 1, containing from about 70 wt. % to about 80 wt. % filler. 21. The composition according to p. 17, wherein the filler is selected from one or more of the following materials: lactose, disubstituted calcium phosphate dihydrate and isomalt. 22. The composition according to p. 21, characterized in that the filler is lactose and disubstituted calcium phosphate dihydrate, or isomalt and disubstituted calcium phosphate dihydrate, or lactose and isomalt. 23. The composition according to p. 22, characterized in that the filler is lactose and disubstituted calcium phosphate dihydrate. 24. The composition according to p. 21, containing from about 5 wt. % to about 80 wt. % lactose. 25. The composition according to p. 24, containing from about 15 wt. % to about 75 wt. % lactose. 26. The composition according to p. 25, containing from about 40 wt. % to about 60 wt. % lactose. 27. The composition according to p. 21, containing from about 15 wt. % to about 50 wt. % disubstituted calcium phosphate dihydrate. 28. The composition according to p. 27, containing from about 15 wt. % to about 30 wt. % disubstituted calcium phosphate dihydrate. 29. The composition according to p. 1, containing from about 2 wt. % to about 15 wt. % binder. 30. The composition according to p. 29, characterized in that the binder is selected from xanthan gum, hydroxypropyl methylcellulose, starch, sodium alginate and povidone. 31. The composition according to p. 30, characterized in that the binder is povidone. 32. The composition according to p. 1, characterized in that the composition further comprises a coloring substance, and in that the granules in cross section have a uniform color. 33. The composition according to p. 32, containing from about 1 wt. % to about 20 wt. % coloring matter. 34. The composition according to p. 1, characterized in that the composition further comprises a flavoring substance. 35. The composition according to p. 34, containing from about 0.05 wt. % to about 5 wt. % flavoring substance. 36. The composition according to p. 1, characterized in that the composition further comprises a sweetener. 37. The composition according to p. 36, containing from about 0.1 wt. % to about 10 wt. % sweetener. 38. The composition according to p. 36, wherein the sweetener is selected from acesulfame potassium, aspartame, sucrose, sucralose, saccharin sodium, sugar, dextrose, fructose, mannitol and xylitol. 39. The composition according to p. 1, containing from about 5 wt. % to about 15 wt. % eslicarbazepine acetate, from about 70 wt. % to about 80 wt. % filler, from about 2 wt. % to about 15 wt. % povidone and from about 1 wt. % to about 10 wt. % colorant, characterized in that the filler contains lactose and disubstituted calcium phosphate dihydrate, in that the composition contains from about 40 wt. % to about 60 wt. % lactose and from about 15 wt. % to about 30 wt. % of disubstituted calcium phosphate dihydrate, and the fact that the granules in the cross section have a uniform color. 40. A method of manufacturing a granular pharmaceutical composition comprising eslicarbazepine acetate, wherein said method comprises: (1) granulating a mixture comprising eslicarbazepine acetate and one or more pharmaceutically acceptable excipients using a first granulating liquid; (2) drying the granules formed in step (1); (3) if necessary, calibrating the size of the granules obtained in step (2); (4) granulating the granules obtained in step (2) or (3) using a second granulating liquid; (5) drying the granules formed in step (4); (6) coating the granules obtained in step (5) using a coating liquid; and (7) drying the coated granules formed in step (6), characterized in that at least 90% of the granules of the composition have a particle size of 1200 μm or less, and at least 90% of the obtained coated granules have a size particles of 90 μm or more, and / or the fact that at least 50% of the obtained coated granules have a particle size of 250 μm or more, where the particle size of these granules is determined by sieving. 41. The method according to p. 40, characterized in that the granulation in step (1) is carried out in a granulator with high shear. 42. The method according to p. 40, characterized in that the granulation in step (1) and the drying of the granules in step (2) is carried out in a fluidized bed dryer. 43. The method according to p. 40, characterized in that the drying of the granules in step (1) is carried out in a fluidized bed dryer. 44. The method according to p. 40, characterized in that step (4) is carried out in a fluidized bed dryer. 45. The method according to p. 40, characterized in that step (6) is carried out in a fluidized bed dryer. 46. The method according to p. 40, characterized in that the first granulating liquid, the second granulating liquid and the coating liquid contain a coloring material. 47. The method according to p. 40, characterized in that the drying of the granules at one or more stages includes drying the granules until the relative humidity of the granules becomes less than 3%. 48. The method according to p. 40, wherein the first and second granulating liquids are aqueous solutions containing a binder selected from xanthan gum, hydroxypropyl methylcellulose, starch, sodium alginate and povidone. 49. The method according to p. 40, characterized in that the first and second granulating liquids are aqueous solutions containing povidone. 50. The method according to p. 40, characterized in that the drying of the granules at each stage is carried out in a fluidized bed dryer and the drying of the granules at each stage is carried out at a supply air temperature and a temperature of granules in the range of from about 50 ° C to about 80 ° C. 51. The method according to p. 42, characterized in that the drying of the granules at each stage is carried out at a drying flow rate of from about 20 to about 90% of the maximum flow rate of the fluidized bed dryer. 52. The method according to p. 42, characterized in that the drying of the granules at each stage is carried out at a drying flow rate of from about 20% to about 50% of the maximum flow rate of the fluidized bed dryer. 53. The method according to p. 40, characterized in that the first and second granulating liquids are added before the start of the corresponding granulation step. 54. The method according to p. 40, characterized in that the rate of addition of the first and second granulating liquids increases over time. 55. The method according to p. 42, characterized in that in the implementation of steps (1), (4) and (6) use a fluidized bed dryer, and the rate of addition of the first and second granulating and coating liquids is from about 0, 02% to about 1% of the total fluid bed dryer per minute. 56. The method according to p. 42, characterized in that in the implementation of steps (1), (4) and (6) a fluidized bed dryer is used, and for delivery of the first and second granulating and coating liquids to the fluidized bed dryer use air. 57. The method according to p. 56, characterized in that the pressure of the air used to deliver liquids is from about 0.1 bar (10 kPa) to about 6 bar (600 kPa). 58. The method according to p. 40, characterized in that the air flow during granulation and coating is enhanced in stages over time. 59. The method according to p. 40, characterized in that when, in the implementation of step (4), a fluidized bed dryer is used, the air flow rate during granulation is from about 10% to about 100% of the maximum flow rate of the fluidized bed dryer. 60. The method according to p. 40, characterized in that when in the implementation of steps (1) (4) and (6) a fluidized bed dryer is used, the temperature of the air supplied to the fluidized bed dryer during granulation or coating is from about 30 ° C to about 80 ° C. 61. The method according to p. 40, characterized in that the temperature of the mixture during granulation in step (1) and / or the temperature of the granules in step (4) or (6) is from about 10 ° C to about 70 ° C. 62. The method according to p. 40, characterized in that step (3) includes a screening step when the granules obtained in step (2) are sieved through a sieve so that the granules have a particle size of about 2 mm or less. 63. The method according to p. 62, characterized in that the granules are sieved through a sieve so that the granules have a particle size of about 0.8 mm or less. 64. The granular pharmaceutical composition obtained using the method according to any one of paragraphs. 40-63. 65. The composition according to any one of paragraphs. 1-39 and 64 for therapeutic use. 66. The composition according to any one of paragraphs. 1-39 and 64 for use in the treatment or prevention of diseases selected from epilepsy, neuropathic pain, migraine, fibromyalgia, and affective disorders. 67. The composition of claim 66, wherein the neuropathic pain is selected from trigeminal neuralgia, phantom pain, diabetic neuropathy, and postherpetic neuralgia. 68. The composition of claim 66, wherein the affective disorder is selected from bipolar disorder.

Images